Representing one of the fastest growing ethnic groups in the United States, Hispanics accounted for 12% of the nation's population by March 2000, and suffer from higher rates of alcohol related problems as compared with those from other ethnic backgrounds (e.g., Caucasians and African Americans). This notwithstanding, genetic factors that might contribute to such risks remain poorly understood. Building upon the research infrastructure that has been established, this competitive continuation application will systematically explore and examine genetic mechanisms for alcoholism in Mexican Americans. This ongoing research program has started to identify unique genetic patterns that might be in part responsible for the heightened risk for alcoholism and alcohol associated health problems in this population. These include (1) extremely low allele frequency for both ALDH2*2 (aldehyde dehydrogenase) and ADH2*2 (alcohol dehydrogenase); (2) a relatively high rate of ADH3*2 and CYP2E1 c2 (cytochrome P4502E1) alleles; (3) association of ADH3*2, ADH2*1, DRD2 (dopamine receptor -141C Del/Ins) and serotonin transporter gene-linked polymorphic region (5-HTTLPR) with alcoholism; (4) a strong association of ADH3*2 and ADH2*1 alleles with binge drinking; and (5) association of the DRD2 Taq1 A and 1B alleles with early age of onset for drinking. In this new funding cycle, we plan to further pursue and clarify the meaning of these findings. Specifically, we will (1) expand our study to include Mexican American women with alcohol problems; (2) further examine the role of these polymorphisms, as well as their potential interactions, in relation to risks for alcoholism in Mexican American populations; (3) examine the role of these risks in relationship with the severity of alcoholism i.e. binge drinking and early onset of drinking; (4) characterize and determine the haplotype of DRD2 in association with drinking in Mexican Americans, and assess the relative advantage of haplotype vs. allelic analysis in delineating risk factors contributory to the development of alcoholism. This study will be the first to systematically examine how genetic factors modulate alcohol dependence and abuse in Mexican Americans. Results derived from such a study should not only provide for a better understanding of alcohol use and abuse among Mexican Americans, but also contribute towards a knowledge base regarding ethnic differences in alcohol pharmacogenetics and mechanisms that might be responsible for the high rate of alcoholism in this minority population. [unreadable] [unreadable] [unreadable]